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Background Tenecteplase (TNK) has emerged as an alternative to alteplase for acute ischemic stroke (AIS) within 4.5 hours, supported by randomized trials demonstrating non-inferiority and improved early reperfusion in select patients. Extended-window thrombolysis guided by advanced imaging has further expanded treatment eligibility. Recent AHA/ASA guidelines suggest that in patients presenting 4.5–9 hours from last known well (LKW) or with wake-up stroke and evidence of salvageable tissue, intravenous thrombolysis may be reasonable. However, CT perfusion (CTP) has technical limitations, particularly in posterior circulation strokes, where small infarct volumes and artifacts may obscure true ischemic risk. MRI DWI–FLAIR mismatch can provide an alternative method to identify viable tissue.Case Description A 41-year-old woman with hypertension, hyperlipidemia, chronic kidney disease, obesity, and migraines presented with acute right-sided weakness, sensory loss, dysphagia, and dysarthria. LKW was 4:00 AM, with presentation approximately 9 hours later. Initial NIHSS was 3. Non-contrast CT was negative for hemorrhage. CTA revealed a long-segment right vertebral artery occlusion, concerning for dissection versus thrombosis. CTP demonstrated no ischemic core or penumbra. Given persistent disabling symptoms, rapid MRI was obtained and showed diffusion restriction in the right lateral medulla without corresponding FLAIR hyperintensity, consistent with DWI–FLAIR mismatch.In the absence of contraindications and given disabling deficits, the patient received TNK (0.25 mg/kg) approximately 9 hours from LKW. Post-thrombolysis monitoring was uneventful. Further workup, including echocardiography and hypercoagulability testing, was unrevealing. Digital subtraction angiography suggested chronic vertebral artery occlusion. Clinically, the patient had resolution of right-sided weakness and sensory deficits, with marked improvement in dysphagia. NIHSS at discharge was 1. She was discharged on dual antiplatelet therapy and high-intensity statin with close follow-up.Discussion This case highlights the successful use of TNK in an extended time window for a posterior circulation stroke guided by MRI DWI–FLAIR mismatch despite negative CTP. Posterior circulation infarcts, particularly in the brainstem, may be underrepresented on perfusion imaging due to technical and anatomical limitations. Additionally, the NIHSS may underestimate clinical severity in these cases, as it is weighted toward anterior circulation deficits and does not adequately capture symptoms such as dysphagia.MRI-based mismatch can identify patients with salvageable tissue when CTP is inconclusive, supporting thrombolysis decisions in carefully selected cases. This is particularly relevant in younger patients, where preventing long-term disability has significant quality-of-life implications. In this patient, treatment likely contributed to avoidance of severe complications such as persistent dysphagia or need for enteral feeding.Conclusion TNK administration in the extended window may be beneficial in selected posterior circulation strokes when guided by MRI DWI–FLAIR mismatch, even in the absence of perfusion abnormalities. This case underscores the importance of individualized, imaging- and symptom-guided decision-making and highlights limitations of both CTP and NIHSS in posterior circulation stroke evaluation.Disclosures S. Patel: None.